Serine is required for a plethora of anabolic processes. Serine is an abundant component of proteins and is required for the synthesis of lipids including sphingolipids and phosphatidylserine, a major component of cellular membranes. Alternatively, serine hydroxymethyltransferases (SHMTs) convert serine to glycine concomitantly charging the folate pool with “one-carbon” units. Both glycine and folate one-carbon units are used to make nucleotides. Thus, serine serves numerous critically important roles in cellular metabolism.
At the cellular level, serine can be imported from the extracellular space via amino acid transporters. Alternatively, serine can be synthesized from glucose via the phosphoserine pathway. De novo synthesis proceeds from the glycolytic intermediate 3-phosphoglycerate (3-PG) via three sequential enzymatic reactions, the first of which is catalyzed by the NAD+ dependent enzyme 3-phosphoglycerate dehydrogenase (PHGDH). For decades, it has been known that cancer cells have enhanced serine synthesis, which contributes to nucleotide synthesis. Recently, focal amplifications of the gene encoding PHGDH have been reported, particularly in breast cancers and melanomas. Additionally, KEAP1 and NRF2 mutant non-small cell lung cancers (NSCLC) overexpress PHGDH. Proliferation of PHGDH amplified cancer cell lines, and other lines that overexpress PHGDH without amplification, is inhibited by PHGDH knockdown. In contrast, lines that express little PHGDH are resistant to shRNA mediated ablation of the pathway presumably because serine import suffices. A detailed mechanistic understanding of why some cancer cells are “acidicted” to serine synthesis despite the availability of extracellular serine for import remains unclear. Interestingly, in triple negative breast cancer (TNBC) and NSCLC, PHGDH amplification and overexpression are associated with more aggressive disease.